Nutritional Approaches to Modulate Cardiovascular Disease Risk in Systemic Lupus Erythematosus: A Literature Review

Systemic lupus erythematosus (SLE) is a chronic pathology characterized by a bimodal mortality pattern attributed to clinical disease activity and cardiovascular disease (CVD). A complex interaction between traditional CVD risk factors such as obesity, dyslipidemia, smoking, insulin resistance, metabolic syndrome, and hypertension, as well as the presence of non-traditional CVD risk factors such as hyperhomocysteinemia, pro-inflammatory cytokines, and C-reactive protein levels, has been suggested as a cause of the high prevalence of CVD in SLE patients. On the other hand, environmental factors, such as nutritional status, could influence the disease’s prognosis; several nutrients have immunomodulators, antioxidants, and anti-cardiometabolic risk properties which could reduce SLE severity and organ damage by decreasing the development of traditional and non-traditional CVD risk factors. Therefore, this critical literature review discusses the therapeutic potential of nutritional approaches that could modulate the development of the main comorbidities related to CVD risk in SLE patients.


Introduction
Systemic lupus erythematosus (SLE) is the prototype autoimmune inflammatory disease characterized by the production of autoantibodies against self-antigens, such as deoxyribonucleic acid (DNA), proteins, and nucleosomes [1]. Notably, cardiovascular disease (CVD) is one of the most important causes of death described in SLE patients [2,3]. Mortality in SLE is characterized by the involvement of traditional and non-traditional CVD risk factors, such as obesity, dyslipidemia, atherosclerosis, and high serum levels of pro-inflammatory mediators. The factors mentioned above could modulate the severity of clinical disease activity, organ damage, and chronicity in SLE [2]. Concerning this, SLE

Materials and Methods
A compressive literature search was performed in the following databases and search engines: PubMed, Europe PubMed Central, and Scielo, considering the period January 1992 to December 2022. The following keywords were used to obtain information on the topics and subtopics: "systemic lupus erythematosus" AND "cardiovascular disease" OR "cardiovascular risk" in combination with the terms: "nutritional status", "nutrients", "polyunsaturated fatty acids", "vitamin A", "vitamin C", "vitamin E", "vitamin B", "vitamin D", "selenium", "polyunsaturated fatty acids", "vitamin C", "vitamin E supplementation", "B vitamins supplementation", "coenzyme Q10 supplementation", "probiotics supplementation", "dietary fiber", "vitamin A supplementation" and "selenium supplementation". Likewise, the methodology and quality of the articles were carefully reviewed, and a complementary bibliography of each selected article was used to find more relevant information. Only English articles were considered. Errata, letters, comments, editorials, and duplicate articles were excluded. Selected articles for the literature review included: original articles; observational and descriptive studies; systematic reviews; critical reviews; meta-analyses; and clinical trials in human and murine models. The article selection methodology is illustrated in Figure 1.
Nutrients 2023, 15, x FOR PEER REVIEW 3 of 20 "cardiovascular risk" in combination with the terms: "nutritional status", "nutrients", "polyunsaturated fatty acids", "vitamin A", "vitamin C", "vitamin E", "vitamin B", "vitamin D", "selenium", "polyunsaturated fatty acids", "vitamin C", "vitamin E supplementation", "B vitamins supplementation", "coenzyme Q10 supplementation", "probiotics supplementation", "dietary fiber", "vitamin A supplementation" and "selenium supplementation". Likewise, the methodology and quality of the articles were carefully reviewed, and a complementary bibliography of each selected article was used to find more relevant information. Only English articles were considered. Errata, letters, comments, editorials, and duplicate articles were excluded. Selected articles for the literature review included: original articles; observational and descriptive studies; systematic reviews; critical reviews; meta-analyses; and clinical trials in human and murine models. The article selection methodology is illustrated in Figure 1.

Cardiovascular Disease Risk Factors in SLE
SLE patients present a high prevalence of cardiovascular risk factors; CVD has even been described as one of the main comorbidities and causes of death in SLE. Several

Cardiovascular Disease Risk Factors in SLE
SLE patients present a high prevalence of cardiovascular risk factors; CVD has even been described as one of the main comorbidities and causes of death in SLE. Several studies have shown that SLE patients have a higher prevalence of traditional risk factors, such as obesity, hypertension, and dyslipidemia, compared with the general population; also, the presence of inflammatory molecules related to SLE, such as C-reactive protein (CRP), inflammatory cytokines, and SLE pharmacotherapy, could contribute to CVD development in SLE [20,21]. In particular, genetic susceptibility to SLE has been reported in Mendelian randomization analyses (MRI) to be associated with increased risk of heart failure, ischemic stroke, and venous thromboembolism [22]. Therefore, a complex interaction between traditional and non-traditional CVD risk factors in SLE, resulting in an exacerbated immune response and persistent inflammation, could play a crucial role in CVD in SLE patients [21,23,24], as we shall see later in the following subtopics ( Figure 2). studies have shown that SLE patients have a higher prevalence of traditional risk factors, such as obesity, hypertension, and dyslipidemia, compared with the general population; also, the presence of inflammatory molecules related to SLE, such as C-reactive protein (CRP), inflammatory cytokines, and SLE pharmacotherapy, could contribute to CVD development in SLE [20,21]. In particular, genetic susceptibility to SLE has been reported in Mendelian randomization analyses (MRI) to be associated with increased risk of heart failure, ischemic stroke, and venous thromboembolism [22]. Therefore, a complex interaction between traditional and non-traditional CVD risk factors in SLE, resulting in an exacerbated immune response and persistent inflammation, could play a crucial role in CVD in SLE patients [21,23,24], as we shall see later in the following subtopics ( Figure 2).

Obesity
Obesity is a chronic inflammatory disease widely linked to CVD in the general population and SLE patients [25]. The connection between obesity and immunity has been widely described; under conditions of excess weight, adipose tissue dysfunction promotes an increase in pro-inflammatory cytokines, such as TNF-α and IL-6 [19].
SLE patients present a high prevalence of excess weight (overweight and obesity), which has been associated with dyslipidemia, atherosclerosis, and higher clinical disease activity than in normal-weight SLE patients [5,25,26].

Dyslipidemia
Dyslipidemia is a common SLE comorbidity; the prevalence of dyslipidemia in these patients can even increase by 60% in the 3 years following diagnosis [27]. SLE patients present higher levels of very low-density lipoprotein-cholesterol (VLDL-C) and TG, and lower HDL-C levels, compared with healthy controls, a phenomenon known as "lupus pattern of dyslipidemia". Similarly, active SLE patients have higher VLDL-C and TG levels, and lower HDL-C and LDL-C levels than inactive SLE patients ("active lupus pattern of dyslipidemia") [9]. The exact mechanisms in the relationship between clinical disease activity and dyslipidemia are not fully understood; however, one of the mechanisms suggested is related to an increase in the number of T follicular helper cells, which stimulates the formation of germinal centers and, subsequently, autoantibody production [28].

Insulin Resistance
There is an association between alterations in glucose levels and CVD. IR could lead to micro-or macroangiopathy, peripheral arterial dysfunction, hampered blood flow, hypertension, and cell dysfunction in cardiomyocytes and endothelial cells; as a consequence, IR may increase the risk for coronary artery disease blockage, stroke, and heart failure [29]. Regarding SLE patients in the USA population, it has been reported that the prevalence of IR is higher in this population compared with healthy controls (29.4% and 19.8%, respectively). SLE treatment (glucocorticoids), obesity, and levels of inflammatory markers may explain the disturbances in glucose levels in SLE [30].

Smoking
Reactive oxygen species in cigarette smoke cause oxidative stress and upregulation of inflammatory cytokines, which play a relevant role in endothelial dysfunction by reducing nitric oxide bioavailability; specifically, superoxide anions can reduce nitric oxide availability through the formation of peroxynitrite and are also associated with LDL-C oxidation, which increases the risk of coronary artery disease and stroke. In SLE patients, smoking has been widely associated with CVD and markers of subclinical atherosclerosis; smoking has even been identified as a risk factor for the progression of coronary artery calcification [31].

Hypertension
Hypertension is one of the main risk factors for CVD in the general population, and the SLE population presents with a high prevalence of hypertension [32,33]. The exact mechanism that predisposes SLE patients to hypertension is still unclear; however, some of the mechanisms suggested are the presence of lupus nephritis, the alteration of vascular endothelial function with subsequent endothelial cell activation, and the increase in endothelin 1, causing renal vasoconstriction and water/sodium retention [33,34].

Sedentary Lifestyle
Physical activity reduces CVD risk and other comorbidities, such as obesity and metabolic syndrome (MetS) [35,36]. Conversely, a sedentary lifestyle can promote the morbidity and mortality associated with chronic degenerative diseases [37].
According to a systematic review conducted in populations in the USA, Brazil, UK, Serbia, Sweden, and Belgium, exercise is not contraindicated in SLE, and it has no deleterious effect on clinical disease activity [38]. However, SLE patients have a high prevalence of inadequate physical activity, which could increase the risk of comorbidities in this population [39].

MetS
MetS is considered an independent risk factor for CVD, and women with MetS have a twofold increased risk of experiencing cardiovascular events. In SLE patients, high MetS prevalence could be related to the inflammatory processes attributed to the pathology of SLE, which contributes to the development of alterations linked to MetS [21]. Further, it Nutrients 2023, 15, 1036 6 of 19 has been described that MetS predisposes SLE patients to new cardiovascular events and vascular mortality, as well as to the development of chronic kidney disease and diabetes mellitus [40].

Hyperhomocysteinemia
Hcy is a nonessential amino acid resulting from methionine transmethylation; a high serum level of this molecule (>15 mmol/L) is considered to be a CVD risk factor, known as hyperhomocysteinemia, and is associated with endothelial damage and vascular disease. One mechanism between CVD and hyperhomocysteinemia is mediated by asymmetric dimethylarginine (ADMA), an endogenous inhibitor of endothelial nitric oxide synthase (eNOS). ADMA causes impaired nitric oxide bioavailability (NO), promoting the uncoupling of eNOS and increasing reactive oxygen species production [41]. SLE patients have elevated levels of Hcy [42,43], which could be related to genetic factors such as methylene tetrahydrofolate reductase (MTHFR) genetic variants such as +677 C > T (rs1801133) and +1298 A > C (rs1801131), or to nutritional factors such as poor consumption of folate and cobalamin, which are necessary for Hcy metabolism [5,26,42,44].

Antiphospholipid Antibodies and Complex Immune Damage
Several autoantibodies and immune complexes have been linked to vascular damage and atherosclerosis in SLE; as such, antiphospholipid (aPL) antibodies-including lupus anticoagulant, anticardiolipin, and anti-β2-glycoprotein I antibodies (anti-β-2GP1)-are associated with thrombotic events driven by immune-mediated mechanisms [45][46][47].
The mechanism that links the presence of aPL antibodies to endothelial injury in SLE is not completely clear; possible pathways include anti-β2-GPI binding to β2-GPI and subsequent endothelial cell activation, and the enhanced formation of foam cells induced by ox-LDL/β2-GPI/anti-β2-GPI immune complex formation [45,48].

Pro-Inflammatory Cytokines
Pro-inflammatory cytokines, such as type 1 interferons (IFN-1) and TNF-α, play a relevant role in the development of atherosclerosis; these cytokines can increase levels of chemotactic proteins and adhesion molecules, which promote the recruitment of monocytes and T cells into the endothelial wall [23].
SLE patients present high levels of type 1 IFNs, mainly IFN-α; this cytokine can reduce endothelial progenitor cells, suppress neo-vascularization in sites of endothelial injury, and may contribute to the development of atherogenesis by enhancing foam cell formation, platelet activation, and plaque rupture. TNF-α, another cytokine involved in SLE pathogenesis, can stimulate monocyte differentiation into macrophages and promote foam cell formation; moreover, high TNF-a levels have been associated with high TG and low HDL-C levels [13,49].

C-Reactive Protein
CRP is an acute-phase reactant produced by the liver under the stimulation of IL-6 and IL-1β. It has been proposed that an alteration in CRP production occurs in SLE, which could induce high CRP levels. The altered levels of CRP in SLE could be related its physiopathology or to the presence of some genetic variants, such as −717 A > G (rs2794521), −409 G > A (rs3093062), +1444 C > T (rs1130864), and +1846 C > T (rs1205) in the CRP gene [50].

Lupus Nephritis
Lupus nephritis is a common alteration in SLE and it is mainly responsible for the deposition of immune complexes in the glomeruli and inflammatory tubulointerstitial changes. In general, it has been reported that 16-45% of SLE patients present with lupus nephritis and about 20% will go on to develop end-stage renal disease [55,56]. However, ethnicity could influence renal manifestations; in this sense, there is evidence to suggest that Black, Hispanic, and Asian/Pacific Island SLE patients have an increased prevalence of renal alterations [57]. In addition, lupus nephritis has been described as a CVD risk factor associated with atherosclerosis in SLE [57] and could increase 2.8-fold the risk of myocardial infarction in this population [58].

SLE Pharmacotherapy Associated with Increased CVD Risk Glucocorticoids
Glucocorticoids can alter mechanisms involved in lipid metabolism. Increased lipolysis; increased LPL and adipokine activity; IR; and free fatty acids β-oxidation inhibition are some of the mechanisms associated with glucocorticoid use [59]. Chronic prednisone administration may influence the development of atherogenic dyslipidemia, mediated by an increase in hepatic lipid synthesis and its mobilization in peripheral tissues. It has been shown that prednisone dose is positively correlated with total serum cholesterol, LDL-C, TG, glucose, arterial blood pressure, and BMI [8]. Moreover, a prednisone dose ≥ 30 mg/day has been correlated with increased serum total cholesterol and TG [9,59].

Methotrexate
Methotrexate is a cytotoxic agent and a folic acid antagonist that depletes intracellular folate levels by the inhibition of key enzymes involved in folate and de novo nucleotide synthesis pathways, such as the Dihydrofolate Reductase (DHFR) and Thymidylate Synthase (TYMS) [60,61]. This inhibition subsequently affects several metabolic pathways, such as the Hcy-methionine pathway [60]. Therefore, methotrexate administration at doses of 10-25 mg per week have been associated with elevated levels of Hcy in rheumatoid arthritis and SLE patients [49,60], which may be counteracted by folic acid supplementation [60].

SLE Pharmacotherapy Associated with Decreased CVD Risk Antimalarials
Antimalarial drugs such as hydroxychloroquine (HCQ) and chloroquine (CQ) have long been used to treat inflammatory rheumatism and SLE; however, their mechanisms of action remain unclear. The mechanism suggested is that these molecules, which are weak bases, interfere with the phagocytosis through an increase in pH in intracellular compartments, disrupting the selective presentation of self-antigens and blocking the proliferative responses of T-cells [62].
Antimalarials, mainly HCQ, have been associated with decreased dyslipidemia [45,62,63], diabetes, and thrombotic events in SLE patients [62]. The mechanism proposed is that antimalarials promote upregulation of the LDL-C receptors, with subsequent enhancement of plasma removal of this lipoprotein and a reduction in hepatic cholesterol synthesis. In animal models, the decrease in LDL-C was explained by the inhibition of lysosomal function, which led to an accumulation of LDL in the lysosome [62,64,65].

Mycophenolate Mofetil
Mycophenolate mofetil (MMF) is another drug used in SLE patients. It is related to low Hcy levels through its ability to decrease the export of Hcy by human proximal tubule epithelial cells, according to an in vitro study [66]. Another mechanism suggested for the way in which MMF influences Hcy metabolism is that mycophenolic acid, an active metabolite of MMF, inhibits the enzyme inosine 5 -monophosphate dehydrogenase; this enzyme participates in purine nucleotide biosynthesis, which is necessary for cell proliferation. The inhibition of cell proliferation causes a decrease in protein turnover and can decrease Hcy levels [66].

Potential Therapeutic Effect of Nutrients in SLE
Environmental factors, such as diet, have a key role in the progress of autoimmune diseases. Diet has become relevant, not only because of its impact on general health but also because nutrients have immunomodulatory, anti-inflammatory, and antioxidant properties that can determine the evolution of several diseases. In this context, diet and nutritional status are modifiable environmental factors involved in SLE pathophysiology that could modulate the response to treatment and the clinical outcomes of the disease [12,15,18]. Therefore, non-pharmacological therapy such as diet might be a safe additional strategy for SLE treatment.
Excess weight and dyslipidemia in SLE patients have been described as associated with clinical disease activity, organ damage, and increased CVD risk [15,17]. In contrast, the potential beneficial role of some nutrients, such as polyunsaturated fatty acids, vitamins A, C, D, and B, and selenium on SLE pathogenesis has been reported in murine models and humans [5,67] (Table 1). Additionally, it has been consistently described that the intake of some nutrients, such as dietary fiber and PUFAs, are directly related to the modulation of traditional risk factors, such as dyslipidemia and hypertension in SLE [68,69]. Likewise, the intake of vitamins B9 and B12 regulate some non-traditional risk factors, such as hyperhomocysteinemia [70,71].

Energy (Calories)
Calorie restriction of around 30-40% may delay expression and ameliorate the progression of autoimmune diseases in the murine model (NZB/NZW) [16]. In the same way, energy restriction maintains CD8+ T and decreases CD4+ T lymphocytes; reduces IL-12, IFN-γ, IgA, and IgG production; delays the onset of kidney disease; and increases life expectancy in response to the downregulation of NF-κβ mRNA expression [16]. Otherwise, restricted consumption of specific amino acids, such as phenylalanine and tyrosine, and a moderate protein intake improves renal function in SLE patients [78]. This improvement is related to the fact that the accumulation of kynurenine (a tryptophan metabolite) and the depletion of cysteine and glutathione in SLE promote the activation of the mechanistic target to rapamycin (mTOR) inflammatory pathway [79]. Therefore, a possible way to reduce inflammation in SLE patients could be the use of mTOR inhibitors, such as acetylcysteine or rapamycin [80,81]. However, because of their side effects they are not the first option for intervention; therefore, calorie restriction could be a safer strategy for reduction in mTOR hyperactivity.

Polyunsaturated Fatty Acids, PUFA (n-3 and n-6)
Dietary lipids, especially polyunsaturated fatty acids, provide energy and are constituents of different tissues. A balance in the consumption of EPA and DHA (3:1 ratio) together with energy restriction has demonstrated a greater anti-inflammatory capacity, reducing the atherogenic lipid profile and reducing the severity of autoimmunity and nephritis compared with a calorie-restricted diet alone, or a PUFA-rich diet alone [82][83][84].
Principal food sources of the PUFAs n-6, and n-3 are oils from plants and seeds-such as corn, soybean, flaxseed-and fish oil [85]. Supplementation with fish oil has been associated with macrophage activity suppression and reduction in pro-inflammatory cytokine expression and cyclooxygenase metabolites, which contribute to the reduction in clinical disease activity and proteinuria and preserve adequate glomerular filtration in animal and human studies [12,86,87]. Moreover, it has been reported that flaxseed inhibits platelet-activating factor, which tends to be elevated in SLE; a daily dosage of 30 g/day appears to reduce total cholesterol by 11% and LDL-C serum levels by 12% [78].
On the other hand, DHA inhibits the action of NF-κβ and TNF-α; reduces anti-double stranded DNA antibody (anti-dsDNA) titers; ameliorates the deposition of IgG in the kidneys; and reduces IL-18 in the NZB/NZW mouse model [88,89]. At the same time, EPA has been demonstrated to reduce IL-1β, IL-6, and TNF-α production, changing cell membrane composition and inhibiting the interaction between receptors and inflammatory cytokines [15,82]. Therefore, PUFAs are considered pro-resolving lipid mediators and have been associated with an enhancement in plaque stability and a reduction in atherosclerosis [90,91].

Vitamin A
Vitamin A (retinoic acid) is an essential micronutrient for the optimal performance of the immune system; it is the active form of all-trans-retinoic acid (ATRA), a nuclear transcription factor that regulates gene transcription and expression [18,92]. Retinoic acid increases the proliferation and cytotoxicity of T cells, specifically regulatory T cells, and inhibits Th17 cell proliferation in murine models [73,92]. The increased ingestion of retinoids has been associated with improving lupus nephritis and proteinuria and with reducing levels of anti-dsDNA in humans and murine studies [73,93]. In female humans, a dose of 100,000 IU of vitamin A daily per two weeks was associated with an immune response improvement [94]; nevertheless, the excessive consumption of vitamin A (>100,000 IU) has been related to anemia, headache, dry skin, nausea, and even death [15,78].

Antioxidant Vitamins (C and E)
Vitamins such as C and E are beneficial in treating SLE because of their antioxidant properties. Vitamin C acts as an immunomodulator, releasing anti-inflammatory mediators [95]. In SLE patients, vitamin C consumption has been inversely associated with clinical disease activity, as vitamin C reduces oxidative stress and suppresses auto-antibody production [70]. On the other hand, a study conducted on SLE women showed that vitamin E supplementation suppressed anti-dsDNA antibodies production. However, no differences were found in DNA oxidative damage, which suggested that vitamin E may decrease autoantibody production through a mechanism independent of its antioxidant activity [96].

B Vitamins
B vitamins can act as coenzymes in two reactions: the remethylation of Hcy to methionine and the isomerization of l-methylmalonyl-CoA; the first reaction occurs in the cytosol and is catalyzed by the methionine synthase enzyme, followed by a l-methylmalonyl-CoA mutase catalysis in the mitochondria [71]. B vitamin deficiency is linked with many patho-logical conditions, such as anemia, megaloblastosis, neuropathy, and neurologic disorders, theoretically linked with hyperhomocysteinemia [15,71].
High levels of homocysteine increase the risk of CVD in patients with SLE; thus, high consumption of vitamins B6, B12, and folate (vitamin B9) may be recommended to promote homocysteine remethylation [70,71]. Supplementation with folate has been associated with SLE symptom improvement and longer life expectancy in a study conducted in mice [97]. Furthermore, a study conducted in SLE children with dyslipidemia showed that niacin (vitamin B3) consumption reduced TG and LDL-C levels [70,98].

Vitamin D
Vitamin D has been implicated in pleiotropic biological functions such as mineral (calcium phosphates) homeostasis and immunomodulation [99,100]. Its deficiency (<20 ng/mL) has been associated with many diseases, including infectious and autoimmune diseases [101].
The immunomodulatory effect of vitamin D has been reported through the activity by various mechanisms of its active metabolite calcitriol (1,25(OH)D 3 ). In in vitro dendritic cells (DCs), the presence of calcitriol keeps DCs in a tolerogenic state; these tolerogenic DCs (tDCs) decrease levels of pro-inflammatory mediators, such as IL-12 and TNF-α, and increase IL-10 production, promoting polarization of T regulatory (Treg) cells [102,103].
A negative correlation has been described between vitamin D (calcidiol) serum levels and clinical disease activity in SLE patients [5,100]. Moreover, vitamin D supplementation in SLE patients (2000, 4000, or 5000 IU weekly for 6 months) caused an increase in Foxp3 expression and a decrease in Th17 cells, thus improving endothelial function [104][105][106]. However, the evidence is still inconclusive; some studies do not support the positive effect of vitamin D supplementation on CVD risk; observational studies have shown that not only calcidiol deficiency, but also very high calcidiol serum levels, could be a risk factor for the development of CVD [107].

Selenium
Selenium is an essential trace element and micronutrient required for numerous aspects of human health. Several of its biological effects occur through the incorporation of selenoproteins, many of which are involved in the activation, proliferation, and differentiation of adaptative and innate immune cells. A study conducted on SLE mouse models showed that selenium supplementation prolongs the life of these mice and promotes the inhibition of activation, differentiation, and maturation of B cells and macrophages, which subsequently reduced anti-dsDNA antibodies. In this regard, such activity could suggest a potential therapeutic selenium supplementation for SLE patients [77].

Nutrients to Target Cardiovascular Disease Risk in SLE Patients
Clinical trials and observational studies have provided evidence about the effects of some nutrient and micronutrient consumption or supplementation on CVD risk factors in SLE [108], as well as in other chronic diseases [109]; it could, therefore, provide a non-pharmacological therapy for SLE patients (Figure 3).

PUFAs
PUFAs are nutrients widely associated with decreasing dyslipidemia in the general population; evidence shows that PUFAs can reduce triglycerides by activating peroxisome proliferator-activated receptors (PPARs) and increase the expression of genes involved in fatty acid oxidation [68]. Randomized interventional trials on SLE patients have reported a decrease in clinical disease activity and an improvement in endothelial function [110,111] ( Table 2). The anti-inflammatory effect of omega-3 fatty acid supplementation has been demonstrated in several clinical trials; it has been shown to significantly reduce inflammatory marker levels and improve both lipid profile and endothelial function [108]. This evidence suggests PUFAs (mainly omega-3 supplementation) as a possible strategy to target inflammation and CVD in SLE. In particular, it has been described that serum concen-trations of PUFA precursors, such as linoleic acid (LA) and α-linolenic acid, are significantly higher in SLE patients compared with healthy controls. Likewise, the concentration of LA has been positively correlated with antinuclear antibody (ANA) titers and doses of corticosteroids; eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) were inversely correlated with anti-dsDNA antibody concentration. Both n-6 and n-3 PUFA precursors may participate in the inflammatory process in SLE patients [112].
pects of human health. Several of its biological effects occur through the incorporation of selenoproteins, many of which are involved in the activation, proliferation, and differentiation of adaptative and innate immune cells. A study conducted on SLE mouse models showed that selenium supplementation prolongs the life of these mice and promotes the inhibition of activation, differentiation, and maturation of B cells and macrophages, which subsequently reduced anti-dsDNA antibodies. In this regard, such activity could suggest a potential therapeutic selenium supplementation for SLE patients [77].

Nutrients to Target Cardiovascular Disease Risk in SLE Patients
Clinical trials and observational studies have provided evidence about the effects of some nutrient and micronutrient consumption or supplementation on CVD risk factors in SLE [108], as well as in other chronic diseases [109]; it could, therefore, provide a nonpharmacological therapy for SLE patients (Figure 3).  (d) Selenium: reduces ADMA concentration, which is considered an independent cardiovascular risk factor due to its capacity to inhibit NO production. (e) Coenzyme Q10: can improve the lipid profile and reduce insulin resistance through modulation of insulin and adiponectin receptors. (f) Probiotics: can deconjugate bile acids which coprecipitate with total cholesterol, to compensate for the loss of bile acids; the liver then converts cholesterol into new bile acids, which can reduce serum total cholesterol levels. (g) B vitamins (B12 and B9): act as cofactors in Hcy metabolism and promote its conversion to methionine, thus decreasing Hcy serum levels. (h) Dietary fiber: its fermentation by gut bacteria provides short-chain fatty acids, such as propionic acid; its absorption decreases cholesterol synthesis in the liver and increases water and sodium absorption into the colonic mucosal cells. SLE: systemic lupus erythematosus; PUFAs: polyunsaturated fatty acids; PPARs: peroxisome proliferator-activated receptors; CVD: cardiovascular disease; ADMA: asymmetric dimethylarginine NO: nitric oxide; Hcy: homocysteine.

Antioxidant Vitamins (C and E)
In SLE, oxidative stress is attributed to the inflammatory process characteristic of the disease, which can induce lipoperoxidation and contributes to the superoxide and hydrogen peroxide production linked to CVD [120,121]. The evidence suggests that vitamin C and E supplementation can reduce lipoperoxidation in SLE patients; however, low consumption and serum levels of these vitamins have been reported in this population [113].

B Vitamins
There is evidence that B vitamins could influence the lipid profile; B6 supplementation in hypertriglyceridemic male patients can reduce total plasma cholesterol, which is attributed to the necessity of B6 for endogenous carnitine synthesis; it has even been reported that a vitamin B6-deficient diet reduces carnitine biosynthesis [122]. The insufficient consumption of B vitamins is also related to increased homocysteine levels, which can induce the development of CVD [26]. In this sense, some studies have shown that complex B supplementation reduces homocysteine levels and decreases the thickness of the carotid artery intima-media wall; therefore, complex B supplementation could be a therapeutic alternative to hyperhomocysteinemia in SLE patients [109,114].

Coenzyme Q10
The coenzyme Q10 (coQ10) is a lipophilic benzoquinone that plays a relevant role in the mitochondrial electron transport chain. It has been reported that coQ10 has beneficial metabolic effects, and the evidence shows that it can improve the lipids profile and reduce insulin resistance. Because of this, coQ10 supplementation has been suggested as a therapeutic alternative for dyslipidemia [115].

Probiotics
Studies in humans have shown a possible link between probiotics and improvement in the lipid profile. The mechanism suggested is that some bacteria, such as L. acidophilus, deconjugate bile acids, which coprecipitate with cholesterol at a pH < 5.5, to compensate for the loss of bile acids; the liver then converts cholesterol into new bile acids, thus reducing cholesterol levels [116].

Dietary Fiber
Dietary fiber is a non-digestible form of carbohydrates; it can be classified either as soluble or insoluble fiber, according to its water solubility properties. Water-insoluble fibers mainly include lignin, cellulose, and hemicellulose, while water-soluble fibers include pectin, gums, and mucilage. The soluble fiber provides a source of short-chain fatty acids, such as propionic acid, which are absorbed from the large intestine; their absorption decreases cholesterol synthesis in the liver and increases sodium and water absorption into the colonic mucosal cells; this could be the mechanism through which dietary fiber has been associated with a reduction in some CVD risk factors, such as systolic blood pressure, visceral adiposity, total cholesterol, and LDL-C serum levels [69,117].

Vitamin A
Vitamin A plays a crucial role in immune responses; in vitro studies have shown a strong suppressive effect on pro-inflammatory Th17 cell function [92]. A clinical trial conducted on atherosclerotic patients who were not taking any medication or suffering from immune disease was randomly assigned to receive either vitamin A or placebo. The results showed that vitamin A supplementation decreased the expression of the IL-17 gene [118]; therefore, it could reduce the inflammatory process and the progression of atherosclerosis in SLE patients.

Selenium
Selenium is an essential micronutrient with antioxidant properties. It has also been suggested that selenium can reduce CVD risk by preventing endothelium oxidative damage. Evidence shows that selenium supplementation reduces ADMA concentration, which is considered an independent cardiovascular risk factor owing to its capacity to inhibit NO production [119].

Limitations and Perspectives
The present study is a literature review; therefore, the search strategy was different from a systematic review. Furthermore, the article selection strategies are not reproducible. On the other hand, some functional foods have demonstrated positive effects on alterations related to CVD and SLE pathogenesis, and they might not have been considered in this study, which was focused on anti-inflammatory and antioxidant properties of micronutrients. Nevertheless, this review provides a qualitative synthesis of the historical and recent evidence about nutrient and micronutrient effects on CVD risk factors and their possible use to target cardiovascular alterations in SLE. Additionally, more cohort studies are necessary to evaluate the risk/benefit ratio of long-term vitamin supplementation in SLE and determine the doses necessary to impact cardiovascular health. It is well known that mega-doses of fat-soluble vitamins, such as A, D, E, and K, may cause toxicity. Therefore, there should be consideration of the upper dose limit in their administration and the presence of serum deficiency, to determine the pharmacological or dietary approaches for their correction and to establish dietary strategies for cardiovascular disease treatment.

Conclusions
CVD is the main complication and cause of death in SLE. The high prevalence of traditional and non-traditional cardiovascular risk factors places this population at high risk of morbidity and mortality for CVD. Based on this, it is vital to identify early CVD risk factors in the SLE population and find alternatives to prevent or reverse them. Studies in animal models and humans have shown that some nutrients positively impact SLE pathogenesis. Moreover, nutrients with immunomodulatory and antioxidant properties could decrease the inflammatory process and indirectly prevent the development of CVD and pro-inflammatory events. Notably, some clinical trials conducted in SLE patients have shown the positive effect of nutritional supplementation on CVD alterations. Therefore, nutrients could provide a successful and safe alternative to reduce CVD risk in SLE; however, more clinical trials are necessary to suggest a cardioprotective diet for SLE patients.